There are three classical opioid receptors, mu (MOP), delta (DOP) and kappa (KOP), which play important physiological and pharmacological roles, especially in pain regulation. Morphine, the prototype MOP agonist, remains the “Gold Standard” for clinical analgesia. The predominant unwanted effects of MOP agonists are their reinforcing effects, which lead to abuse and physical dependence. These effects are important for another major use of MOP agonists—the treatment of opiate abuse and dependence as less dangerous heroin substitutes on which addicts can be stabilized before detoxification.
In 1994, a fourth member of the GPCR family of opioid receptors was discovered, followed soon after by the isolation of its endogenous ligand, nociceptin. Though sharing a high degree of amino acid homology with the classical opioid receptors, affinity for the nociceptin (NOP) receptor among clinical opioids has been shown only in the case of buprenorphine. NOP ligands have been shown to have antidepressant activity, antianxiety effects and the ability to modulate MOP agonist-induced development of tolerance and physical dependence when MOPr and NOPr agonists are co-administered. (Whiteside and Kyle, 2013) (Mustazza and Bastanzio, 2011).
Despite substantial research investment in the field by several pharmaceutical companies, to date no NOP selective ligand has progressed through to clinical practice. Recent research activity has been focused on bifunctional MOP/NOP agonist ligands based on the hypothesis that since NOP agonists block development of tolerance and physical dependence to MOP agonism, ligands having both NOP and MOP agonism should maintain analgesic activity but show less tolerance and addiction liability. Design strategies have started from leads with MOP or NOP agonist selectivity onto which the alternative affinity/efficacy is grafted. KOP antagonists have been shown in preclinical and clinical studies to have potential as antidepressants and for the prevention of relapse in recovering cocaine addicts. For example, the KOPr antagonists norBNI and JDTic have been shown to block stress-induced potentiation of cocaine place preference (McLaughlin et al, 2003) and to block footshock-induced reinstatement of cocaine self-administration behaviour (Beardsley et al, 2005; Redila and Chavkin, 2008). KOPr antagonists have also been shown, in rats, to selectively attenuate ethanol-dependent self-administration while leaving nondependent ethanol self-administration unaffected (Walker and Koob, 2008). This appears consistent with earlier findings of a decrease in alcohol self-administration in KOR knockout mice (Kovacs et al, 2005). KOP receptor antagonists have also demonstrated efficacy in various models of stress related psychiatric illnesses including anxiety, depressive disorders, and addiction (Van't Veer and Carlezon Jr, 2013).
MOP antagonism in agents lacking any MOP agonism (zero efficacy), exemplified by naltrexone (1a), nalmefene (1c), β-naltrexol (1b) and desoxonaltrexone (1d) has given rise to clinical use of 1a and 1c for the treatment of alcohol abuse and dependence and for the prevention of relapse in detoxified opiate addicts. These ligands display little or no affinity for NOP receptors.